Medaka Fish Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. PD is pathologically characterized by dopamine (DA) neuron loss in the substantia nigra pars compacta (SNpc), accompanied by α-synuclein aggregates known as Lewy bodies. Animal models are indispensable for elucidating the pathological mechanisms of diseases and developing new treatments. However, a lack of animal model that faithfully replicates PD has been a major barrier to overcoming this disease. Here, we present novel animal models of PD in medaka fish. Teleost fish have DA neurons that correspond to those observed in humans within the SNpc, allowing us to evaluate their phenotypes as PD models. We have developed several animal models of PD in medaka fish via toxin or genetic modification. In our models, we found that dopaminergic neurotoxins caused DA neuron loss and a reduction of spontaneous swimming movement, suggesting the potential utility of medaka fish as an animal model of PD. Administration of proteasome or lysosome inhibitors resulted in DA neuron loss accompanied by ubiquitin-positive cytosolic inclusion bodies, suggesting that DA neurons are vulnerable to proteasome or lysosome dysfunction. Several lines of medaka fish with mutations in the causative genes of rare familial PD demonstrated that mitochondrial dysfunction and impairment of the autophagy–lysosome pathway are involved in the development of PD. In this review, we outline PD medaka models we have developed and discuss future perspectives on medaka fish as a PD model.

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Acknowledgment

These works were mainly supported by the Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (JST); by Grant-in-Aid for Specially Promoted Research and Scientific Research on Innovative Areas “Brain Environment” from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and by JSPS KAKENHI Grant Number JP15H02540. We thank Dr. Hideaki Matsui, who conducted many of the studies introduced here. We also thank Drs. Masato Kinoshita, Tomoko Ishikawa-Fujiwara, Takeshi Todo, and Shunichi Takeda for their excellent collaborations.